Osteoporosis is defined as a “disorder characterized by decreased bone strength and high risk for bone fracture”. Bone fracture often occurs at metaphyseal region of limb bones or at spine. In particular, femoral neck fracture, vertebral fracture, distal radial fracture, and proximal humeral fracture are the four major fractures caused by osteoporosis. In general, due to fragile nature of a bone, bone fracture accompanied with osteoporosis cannot be completely cured by a treatment. In addition, there is other problem that a sufficient level of fixation cannot be obtained even when osteosynthesis is carried out. Further, a various kind of serious complications such as muscle weakness, articular contracture, decubitus ulcer, dementia, urinary tract infection, impaired cardiopulmonary function and the like may easily occur due to disuse of a human body which follows the fracture. Still further, an unfavorable cycle in which simultaneous occurrence of disuse bone atrophy causes further progress in osteoporosis may not be avoided.
As described in the above, bone fracture that is accompanied with osteoporosis impairs quality of life (QOL) of patients, and also has a significant effect on prognosis. At the same time, it imposes significant social problems relating to attending patients and high medical cost, etc. Therefore, object of treating osteoporosis is to accelerate bone formation so that bone mass is increased and bone fracture is prevented.
Until now, as a prophylactic and/or therapeutic agent for osteoporosis, estrogen preparation, a selective estrogen receptor modulator (SERM) like raloxifen, etc., a calcitonin preparation like elcatonin, etc., and a bisphosphonate preparation like alendronate, etc., have been clinically used. Most of these preparations contribute to increasing bone mineral density during bone remodeling process by inhibiting bone resorption. Recently, excellent efficacy of a parathyroid hormone (PTH) preparation, which restores a lost bone dimension by actively stimulating bone formation, is getting new attention.
To a patient having postmenopausal osteoporosis who had been already suffering from vertebral body fracture, PTH (20 μg) was administered subcutaneously everyday for 19 months in average. As a result, bone mineral density was increased as much as 9.7% in lumbar spine (1.1% for placebo administration group), and 2.8% in neck of femur (−0.7% for placebo administration group). In addition, frequency of occurrence of new vertebral body fracture was inhibited as much as 65% and frequency of occurrence of non-vertebral body fracture was also inhibited as much as 53% [Non-patent Document No. 1]. Considering that the inhibitory effect of an agent for inhibiting bone resorption, such as bisphosphonate, raloxifen and the like, on vertebral body fracture is about 50% when it is administered for 3 to 4 years, bone fracture inhibiting effect of PTH is believed to be very potent. In fact, from a comparative test in which PTH (20 μg, subcutaneous injection everyday) or alendronate (ALN; 10 mg, oral administration everyday) was administered to a patient having postmenopausal osteoporosis, it was found that bone mineral density of lumbar spine was increased up to 10.3% for PTH administration group 18 months after the administration, while only 5.5% increase was recognized for the ALN administration group [Non-patent Document No. 2], thus indicating potent efficacy which has not been obtained from previous drug compounds. However, the PTH preparation is a peptide preparation and needs to be subcutaneously injected to a subject every day. Thus, as an administration method for patients suffering from osteoporosis, who are predominantly elderly people, it is not necessarily a convenient method. For such reasons, several attempts are made to provide compliance of dosing and convenience for patients, such as developing a preparation which can be administered once a week (Non-patent Document No. 3), developing an intranasal dosage preparation (Non-patent Document No. 4), etc. A study relating to an antagonist for a calcium-sensing receptor is one of such attempts.
Calcium-sensing receptor (CaSR) is a G protein coupled receptor which was cloned in 1993, and it plays an essential role for the control of PTH secretion in parathyroid gland. Activation of CaSR by extracellular calcium (Ca) inhibits secretion of PTH via activation of Gq protein [Non-patent Document No. 5]. In this connection, an idea of producing a preparation that can promote secretion of PTH by inhibiting CaSR function was presented. In fact, the first antagonist for CaSR was reported by Gowen et al. (Non-patent Document No. 6). As a result of single oral administration of an antagonist for CaSR referred to as NPS2143 to a rat, Gowen et al. confirmed that PTH concentration in blood is continuously increased. Further, after the oral administration of NPS2143 to a model rat having osteoporosis (rat with removed ovary) everyday for eight weeks, they also learned that bone formation evaluated by bone morphometry is increased but bone mineral density remained almost the same. Meanwhile, when NPS2143 and estrogen are administered together, increase in bone resorption that was found for administration of NPS2143 only was inhibited, and even compared to a group administered with estrogen only, a significant increase in bone mineral density was found. In general, it is believed that intermittent administration of PTH increases bone mineral density while continuous administration of PTH decreases it [Non-patent Document No. 7]. As such, it was considered that the reason why no activity of increasing bone mineral density was found when only NPS2143 was administered is due to the persistent activity of increasing the PTH concentration in blood by the compounds. Therefore, unlike NPS2143, an ideal antagonist for CaSR preferably has a transient activity of increasing PTH concentration in blood. Further, an essential requirement for an ideal antagonist for CaSR includes excellent safety having no cell toxicity, mutagenicity, drug interaction, etc. However, at the present moment there is no antagonist for CaSR that is approved as a pharmaceutical preparation by authorities.
Meanwhile, as a compound which has a similar function as the compounds of the present invention, those disclosed in the following Patent Documents have been known. However, they are all different from the compounds of the present invention in terms of characteristics of a chemical structure.
[Prior Art Literatures]
[Non-Patent Document]
[Non-patent Document No. 1] Neer R M., et al., N. Engl. J. Med. 344. 1434-1441. 2001.
[Non-patent Document No. 2] McClung M R., et al., Arch. Intern. Med. 165. 1762-1768. 2005.
[Non-patent Document No. 3] Miki T., et al., J. Bone Mineral Metab. 22. 569-576. 2004.
[Non-patent Document No. 4] Matsumoto T., et al., Osteoporosis Int. 17. 1532-1538. 2006.
[Non-patent Document No. 5] Brown E M., et al., Nature. 366. 575-580. 1993.
[Non-patent Document No. 6] Gowen M., et al., J. Clin. Invest. 105. 1595-1604. 2000.
[Non-patent Document No. 7] Uzawa T., et al., Bone 16. 477-484. 1995.
[Patent Document]
[Patent Document No. 1] International Publication No. WO97/37967 pamphlet
[Patent Document No. 2] International Publication No. WO02/14259 pamphlet
[Patent Document No. 3] International Publication No. WO04/69793 pamphlet
[Patent Document No. 4] International Publication No. WO04/106296 pamphlet
[Patent Document No. 5] International Publication No. WO04/047751 pamphlet
[Patent Document No. 6] International Publication No. WO04/017908 pamphlet